Lubiprostone is an active pharmaceutical ingredient in the drug product Amitiza® for the treatment of diseases such as chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. Lubiprostone is categorized as a more unstable prostaglandin E1, and is easily and rapidly degraded to prostaglandin A1, hereinafter referred to as impurity A, under acid or alkaline conditions or even at room temperature as shown in the following Scheme A:

Therefore, both the preparation method and the purification process of Lubiprostone generate a certain amount of impurity A as shown in Scheme A. Impurity A has been identified as the major degradation products or impurity of Lubiprostone. Although impurity A can be removed by silica gel chromatography, additional impurities A will be regenerated in the purified Lubiprostone solution during the subsequent high-temperature, long-duration concentration process. Given this, it has been noted that the best final purification step for industrial mass production of Lubiprostone is crystallization, which does not require high temperatures or a long-duration concentration process.
Many prior art references show crystallization methods for Lubiprostone, but none discloses amounts of impurity A either before or after crystallization. The prior art references focus on the types of crystalline forms of Lubiprostone. Thus, the benefits of conventional crystallization methods for purifying Lubiprostone cannot be evaluated based on the prior art references.
For example, WO 2009/121228 discloses a crystalline form of Lubiprostone, hereinafter referred to as Lubiprostone crystal I, which can be obtained using various low boiling point solvent systems, such as ethyl acetate/n-hexane, acetone/n-hexane, dichloromethane/n-hexane, isopropanol/n-hexane, acetone/water, and methanol/water. Solvents with low boiling points have typically been used for crystallization because they are easily removed from the resultant crystals simply by allowing the solvent to evaporate. The Lubiprostone crystal I has an X-ray powder diffraction pattern as shown in FIG. 1 and a differential scanning calorimetry pattern comprising an endothermic peak with a peak onset temperature of 59.34° C. and a peak maximum of 60.97° C.
US 2010/056808 discloses a crystalline Lubiprostone, hereinafter referred to as Lubiprostone crystal II, obtained in a solvent system of isopropyl acetate/heptane. US 2010/056808 teaches that two crystallographically independent molecules, enantiomorphs, were found by optical microscope in the unit cell of Lubiprostone crystal II. US 2010/056808 further discloses that an ideal powder pattern was calculated from the single crystal data; this pattern is shown in FIG. 2 and FIG. 3 of the accompanying drawings. Upon comparison, it is found that the pattern shown in FIG. 3 is consistent with that of FIG. 1, so the polymorph B of Lubiprostone shown in FIG. 3 (i.e., FIG. 3 of US 2010/056808) might be the same as Lubiprostone crystal I. However, US 2010/056808 does not directly illustrate the X-ray powder diffraction spectrum of Lubiprostone crystal II. Moreover, US 2010/056808 neither teaches the amount ratios of the two enantiomorphs, nor indicates which enantiomorph is the crystalline form of Lubiprostone.
WO 2011/091513 discloses another crystalline form of Lubiprostone, i.e., APO-II, hereinafter referred to as Lubiprostone crystal III, which has an X-ray powder diffraction diffractogram as shown in FIG. 4 and a differential scanning calorimetry thermogram comprising an endothermic peak with a peak onset temperature of approximately 76° C. and a peak maximum of approximately 77° C.
CN 104710398 discloses a further Lubiprostone crystal form, hereinafter referred to as Lubiprostone crystal IV, which has an X-ray powder diffraction pattern as shown in FIG. 5 and a differential scanning calorimetry pattern comprising a peak maximum of 58±2° C.
Consequently, there is a demand for crystallization methods for the efficient and economical preparation of high-purity Lubiprostone crystals such that undesirable impurities, particularly impurity A, can be effectively reduced or avoided or can be easily removed during the crystallization purification method.